Department of Chemistry, Washington State University, Pullman, WA 99164-4630, USA.
Arch Biochem Biophys. 2010 May;497(1-2):68-81. doi: 10.1016/j.abb.2010.03.011. Epub 2010 Mar 25.
One goal in drug design is to decrease clearance due to metabolism. It has been suggested that a compound's metabolic stability can be increased by incorporation of a sp(2) nitrogen into an aromatic ring. Nitrogen incorporation is hypothesized to increase metabolic stability by coordination of nitrogen to the heme-iron (termed type II binding). However, questions regarding binding affinity, metabolic stability, and how metabolism of type II binders occurs remain unanswered. Herein, we use pyridinyl quinoline-4-carboxamide analogs to answer these questions. We show that type II binding can have a profound influence on binding affinity for CYP3A4, and the difference in binding affinity can be as high as 1200-fold. We also find that type II binding compounds can be extensively metabolized, which is not consistent with the dead-end complex kinetic model assumed for type II binders. Two alternate kinetic mechanisms are presented to explain the results. The first involves a rapid equilibrium between the type II bound substrate and a metabolically oriented binding mode. The second involves direct reduction of the nitrogen-coordinated heme followed by oxygen binding.
药物设计的一个目标是降低因代谢引起的清除率。有人提出，在芳环中引入 sp2 氮可以增加化合物的代谢稳定性。氮的掺入被假设通过氮与血红素铁的配位（称为 II 型结合）来增加代谢稳定性。然而，关于结合亲和力、代谢稳定性以及 II 型结合物的代谢如何发生的问题仍未得到解答。在这里，我们使用吡啶基喹啉-4-甲酰胺类似物来回答这些问题。我们表明，II 型结合可以对 CYP3A4 的结合亲和力产生深远影响，结合亲和力的差异高达 1200 倍。我们还发现，II 型结合化合物可以被广泛代谢，这与假设的 II 型结合物的无终末复合物动力学模型不一致。提出了两种替代的动力学机制来解释这些结果。第一种涉及 II 型结合底物与代谢定向结合模式之间的快速平衡。第二种涉及氮配位血红素的直接还原，然后是氧结合。
